Despite remarkable advances in therapy of leukemia over the past 3 decades, the majority of adult patients with leukemia die from complications of their disease or therapy. There is convincing evidence that leukemia, like other cancers in humans, is the consequence of multiple mutations. Although significant strides have been made in identification of genes implicated in pathogenesis of leukemia over the past decade, little is known about the initiating events in the pathogenesis of leukemia. The deficit in our understanding of the early events in the molecular pathogenesis of leukemia is due in part to the rarity of familial predisposition to leukemia. In contrast with cancers such as breast and colon cancer, in which an inherited cancer predisposition has allowed for linkage analysis and positional cloning of the "first hit" mutations transmitted in the germline, there are few leukemia-prone families that would allow for an analogous approach. However, we have identified an extended pedigree characterized by a predisposition to develop leukemia. Furthermore, the trait is "marked" at birth by a platelet defect that has allowed for reliable identification of affected individuals. The goal of this proposal is to identify the gene that is responsible for this inherited leukemia syndrome, which in turn may provide critical information about the early genetic events in the pathogenesis of leukemia. Using a generalized linkage approach, we have localized the gene that causes the inherited predisposition to leukemia to a small region of human chromosome 21q22.1. In addition, we have recently identified a second pedigree with the same clinical phenotype which also demonstrates linkage to chromosome 21q22.1. Thus, there is convincing evidence to implicate this locus in pathogenesis of inherited leukemias. The goal of this proposal is to identify the gene which is responsible for the familial platelet disorder with propensity to develop AML. Our approach, as detailed in the body of the proposal, will focus on mutational analysis of genes which map to this region. Based on experience with other inherited cancers, we would predict that mutations in the FPD disease gene will also be relevant in sporadic leukemias, and will provide valuable information about the early genetic events in leukemia. In turn, this information may provide insight into novel therapeutic approaches to treatment of leukemia.